The circulating level of C-reactive protein (CRP) is a strong predictor of endothelial dysfunction and hypertension in humans. We have demonstrated in transgenic CRP mice (TG-CRP) that CRP causes endothelial NO synthase (eNOS) downregulation, endothelial dysfunction and hypertension. Cell culture studies indicate that CRP also impairs insulin signaling to eNOS, and in preliminary studies we have discovered that TG-CRP mice are insulin resistant. Further work in double transgenic mice indicates that CRP-induced hypertension is mediated by the inhibitory IgG Fc? receptor (Fc?R), Fc?RIIB, and we now have direct evidence of endothelial cell expression of Fc?RIIB protein. Considering the important link between endothelial dysfunction and insulin resistance in numerous inflammatory conditions, the overall hypothesis to be tested in the proposed research is that CRP actions via endothelial Fc?RIIB cause both hypertension and insulin resistance. Aim 1 is to determine the role of endothelial Fc?RIIB in CRP-induced hypertension. The receptor will be deleted in endothelium by crossing floxed Fc?RIIB mice (Fc?RIIBflox/flox) with mice expressing tamoxifen-inducible Cre-recombinase under the regulation of the vascular endothelial cadherin promoter (VECad-Cre-ERT2). Fc?RIIBflox/flox:VE-Cad-Cre-ERT2 will be crossed with TG-CRP mice, and BP will be measured by radiotelemetry. Related changes in vascular gene expression will also be assessed, and the novel mechanisms by which Fc?RIIB potentially modulates endothelial gene expression will be investigated. Aim 2 is to determine the basis for CRP-induced insulin resistance. We will perform glucose- and insulin-tolerance tests, hyperinsulinemic-euglycemic clamps evaluating glucose infusion rate, glucose disposal rate and endogenous glucose output, and skeletal muscle glucose uptake studies in TG-CRP mice and in crosses of TG-CRP and Fc?RIIB-/- mice. Body weight and composition, food intake, and energy expenditure will also be evaluated. Aim 3 is to determine the mechanistic linkage between the endothelial actions of CRP and CRP-induced insulin resistance. Insulin-induced skeletal muscle bloodflow will be evaluated in TG-CRP mice, and euglycemic clamps will be done in the Fc?RIIBflox/flox:VE-Cad-Cre-ERT2:TG- CRP mice and controls from Aim 1. We will also determine if molsidomine or Sildenafil treatment to overcome diminished NO bioavailability in TG-CRP mice normalizes insulin sensitivity. By meeting these aims, we will increase our basic understanding of how CRP participates in the pathogenesis of hypertension and insulin resistance. The new knowledge gained about endothelial Fc?RIIB will also be valuable in understanding why immune complex-mediated diseases such as rheumatoid arthritis and lupus are complicated by both cardiovascular disease and insulin resistance. We anticipate that the proposed work will lead to new therapies capable of simultaneously optimizing endothelial cell function, blood pressure and glucose metabolism in a variety of clinical conditions. PUBLIC HEALTH RELEVANCE: Elevations in the circulating level of C-reactive protein (CRP) are a strong predictor of the development of hypertension and insulin resistance. The proposed research program will determine how CRP and its cell surface receptors cause hypertension and insulin resistance.